Process for treating a patient by medicinal therapy by a film-shaped therapeutic system

ABSTRACT

A process for treating a patient by medicinal therapy by a film-shaped therapeutic system. The process comprises the steps of applying a film-shaped therapeutic system comprising at least three layers connected with each other onto the oral mucosa of a patient in need of medicinal therapy for a period of up to 24 hours and releasing the active substance with an initial burst dose and a subsequent maintenance dose. The film-shaped therapeutic system comprises at least three layers connected with each other for transmucosal administration of active substances. The system has a layer which is mucoadhesive in an aqueous environment and a backing layer which is at least two-layered. At least one of these layers contains an active substance. The mucoadhesive layer is capable of swelling in an aqueous media, but is insoluble or only poorly soluble in an aqueous media.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of application U.S. Ser.No. 10/533,835 filed on May 4, 2005 (now U.S. Pat. No. 8,808,729 issuedon Aug. 19, 2014), which is a 371 National Stage application ofInternational Application No. PCT/EP2003/012272 filed on Nov. 4, 2003,which claims priority of German application number 102 52 726.1 filed onNov. 13, 2002, all of which are incorporated herein by reference intheir entireties.

BACKGROUND OF INVENTION

1. Field of the Invention

The invention relates to a multilayered film-shaped therapeutic systemfor transmucosal administration of active substances, especially ofmedicinal substances. These systems are suitable for rapid delivery ofactive substances over. a prolonged period in a controlled manner.

2. Description of the Prior Art

Mucoadhesive medicament forms are known in the state of the art forexample in the form of mucoadhesive tablets, disks or film-shapedadministration forms. Some of those medicament forms are alreadyavailable on the market. Mucoadhesive medicament forms are applied tothe mucosa, especially to the oral mucosa (buccal and/or gingivalmucosa), thereby enabling the delivery of the active substance containedtherein and absorption via the mucosa. It is advantageous here that theactive substances enter the circulation quickly and a quick onset ofaction can be achieved. Medicament forms of this kind are suitable, inparticular, for administering such active substances that are poorlyabsorbed by the gastrointestinal tract and/or exhibit a short plasmahalf-life.

The best known mucoadhesive administration forms are tablets which areconfigured in two layers and consist of a mucoadhesive layer and aretarding backing layer (AFTAB®, Rottapharm). There have been endeavoursto improve the functional capability of such mucoadhesive tablets, forexample by providing drainage notches which enable saliva liquid to betransported away from the application site. Such tablet systems areindeed capable of fulfilling their function, but they are experienced asunpleasant to the patients since they are relatively thick, hard andinflexible, and thereby induce a marked foreign body sensation.

Apart from the above, mucoadhesive “disks” are known which can beformulated on the basis of lipophile, insoluble polymer matrices andhydrophile mucoadhesive polymers and, if required, surfactants. Thesedisks usually have a thickness of approx. 1 mm and therefore cause anunpleasant foreign body-sensation in the mouth.

From U.S. Pat. No. 4,713,243 there are known mono- or multilayeredmucoadhesive films whose mucoadhesive layer consists of hydroxypropylcellulose, an ethylene oxide homopolymer, a water-insoluble polymer(e.g. ethyl cellulose, propyl cellulose, polyethylene, polypropylene)and a plasticizer. These administration forms are considered morepleasant by the patients, but their usefulness is highly restricted onaccount of the only short period of adhesion. This short duration ofadhesion is due to the fact that the polymers employed are readilysoluble in water, so that no appreciable retardation of adhesion doesoccur. To achieve that the mentioned mucoadhesive films adhere to themucosa for a prolonged period of time, the content of water-insolublepolymer components (e.g. ethyl cellulose, propyl cellulose) in theformulation must be increased. However, as a consequence, themucoadhesive systems thus produced have a greater thickness, whichincreases the foreign body sensation during the period of application.In addition, the greater thickness entails a decrease in the release ofactive substance since the diffusion paths become longer and thediffusion coefficients diminish.

It has also been proposed (Patent No. U.S. Pat. No. 5,719,197) toimprove the coherence of mucoadhesive systems by using clay as anadditive. However, such clays must be regarded as disadvantageousbecause of their property of adsorbing certain active substances or ofaffecting the active substance stability by catalytic effects.Furthermore, the weight and thickness of the system is markedlyincreased by these additives.

The task underlying the present invention was thereby to providemucoadhesive administration forms which do not have the above-mentioneddisadvantages, in particular inducement of a foreign body sensation,insufficient active substance release and too short a duration ofadhesion.

Furthermore, these mucoadhesive medicament forms are to enable a quickonset of action on the one hand and on the other hand, enable acontinuous and controlled active substance delivery over a prolongedperiod of time.

SUMMARY OF THE INVENTION

This task is surprisingly solved by film-shaped, at least double-layeredtransmucosal therapeutic systems according to the present invention andthe alternative embodiments of the present invention.

The inventive therapeutic systems which are suitable, in particular, fortransmucosal administration of active substances have a structure of atleast two layers which are connected with each other. At least one ofthese layers contains active substance. One of the two sides of theinventive system is limited by a mucoadhesive layer which optionallycontains active substance or is free of active substance. Duringapplication, this mucoadhesive layer is in contact with the absorbingmucosa, e.g. oral mucosa. The mucoadhesive layer of the system isconnected with a backing layer which is mono-layered or double-layeredand which may serve as an active substance reservoir. A special propertyof the mucoadhesive layer consists in the fact that it is capable ofswelling in aqueous media, but is insoluble or only poorly, i.e. slowly,soluble therein. The insolubility or reduced solubility increases theperiod of adhesion to the mucosa, thereby enabling an active substancerelease that lasts for a prolonged period of time. Since the inventivesystems are film-shaped and may have a thickness of less than 1 mm, theydo not cause a foreign body sensation and are not unpleasant to thepatients. Therefore, the acceptance of such medicament forms isimproved.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic cross-section view of the structure of layers of afirst embodiment of the mucoadhesive system according to the presentinvention.

FIG. 2 is a schematic cross-section view of the structure of layers of asecond embodiment of the mucoadhesive system according to the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

It should be appreciated that the term “aqueous media” means, inaddition to water, physiological liquids, such as saliva.

Referring to FIG. 1 a system 1 is provided as a double-layered structurecomprising a mucoadhesive layer or adhesive layer 2 and a backing layeror reservoir layer 3 connected to said mucoadhesive layer or adhesivelayer 2. Mucoadhesive layer 2 of system 1 is in adhesive contact with amucosa 4; status during application.

Turning now to FIG. 2, system 1 is provided as a three-layered structurecomprising a mucoadhesive layer 2 and a backing layer 3. Backing layer 3consists of two individual reservoir layers 3 a, 3 b. Reservoir layer 3a is a middle layer 3 a and reservoir layer 3 b is an outer layer orboundary layer 3 b. The reservoir layer 3 b, closing the system towardsthe outside, is configured so as to be diffusion-controlled.

The mucoadhesive layer 2 consists mainly of a polymer mixture which isfilm-forming, swellable in aqueous media but non-soluble or only poorlysoluble therein. The polymer mixture comprises at least one hydrophile,mucoadhesive polymer embedded or dispersed in a polymer matrix.Optionally, the mucoadhesive layer 2 may contain active substance(s) oradditives.

The aforementioned hydrophile polymer, respectively the hydrophilepolymers is/are selected from the group comprising hydrophile adhesivepolymers carrying carboxyl groups, polyacrylates or polyacrylic acidderivatives (e.g. CARBOPOL® types, from the firm of B.F. Goodrich) andtheir salts, carboxymethyl cellulose and its salts, poly(methyl vinylether maleic anhydride) and its aqueous or alcoholic hydrolysates andsalts (e.g. GANTREZ® types, such as GANTREZ -AN, -S, -ES, -MS; fromISP).

The above-mentioned polymer matrix of the mucoadhesive layer isessentially based on polymers which are hydrophilic, but insoluble orslowly soluble in an aqueous media. This polymer or these polymersis/are selected from the group of polyvinyl alcohols and polyacrylates.Other polymers known to those skilled in the art which enable ananchorage of the mucoadhesive layer 2 on the adjacent backing layer 3that is durable in dry condition or in aqueous environment, may also beutilized.

To ensure a durable connection between the mucoadhesive layer 2 and thebacking layer 3 superimposed thereon (respectively one of the individuallayers 3 a, 3 b of the backing layer 3, in the case of a multi-layeredbacking layer) it is advantageous to select base polymers which areidentical with those polymers employed for preparing the backing layer3, or are at least chemically allied thereto.

Neighbouring layers of the film-shaped system contain one or moreidentical or chemically allied base polymers which are selected from thegroup of the polyacrylates.

In this way it can be ensured that for the period of application themucoadhesive layer 2 remains durably connected with the backing layer 3,even in aqueous environment (oral cavity).

According to one embodiment of the present invention, the polymers ofthe mucoadhesive layer 2 are crosslinked by employing physical or/andchemical methods. By cross-linking, the degree of solubility can bereduced without affecting hydrophilicity. In this way it is possible toadditionally, and with particular advantage, further improve theduration of adhesion to the mucosa 4. Suitable crosslinking reagents andcrosslinking processes are known to those skilled in the art (e.g. useof aluminium acetylacetonate or titanyl acetylacetonate as crosslinkingagent).

The mucoadhesive layer 2 may contain additives suitable for modulatingthe adhesive properties. It should be appreciated that these are knownto those skilled in the art.

The backing layer 3 or (in the case of a multilayer backing layer) theindividual layers 3 a, 3 b of the backing layer 3 is/are produced on thebasis of polyacrylates, especially on the basis of neutralisedpolymethyl methacrylates (e.g. EUDRAGIT® E 100, EUDRAGIT® NE 30 D,PLASTOID® B; Röhm Pharma). For example, po)yacrylates which are capableof swelling in aqueous media—largely independently of the pH value—, butare not soluble therein may be employed. The backing layer 3 or at leastone of the layers 3 a, 3 b forming the backing layer 3 may optionallycontain one or more auxiliary substances, for example selected from thegroup of the plasticizers, penetration enhancers, solubilizers,colorants, pigments and matrix formers. It should be appreciated thatsuitable substances are known to those skilled in the art.

Suitable as plasticizers are, for instance, plasticizers from the groupcomprising hydrocarbons, alcohols (especially higher alcohols such asdodecanol, undecanol, octanol), polyhydric alcohols, polyethyleneglycols, triglycerides, carboxylic acids, derivatives of carboxylicacids, ethers, esters (e.g. diethyl phthalate, n-butyl adipate, citricacid esters) and amines.

Suitable as absorption or permeation enhancers are, in particular,substances selected from the group comprising the following substancesand substance classes: saturated or unsaturated fatty acids, fatty acidesters, especially esters with methanol, ethanol or isopropanol (e.g.oleic acid ethyl ester, oleic acid methyl ester, lauric acid methylester, lauric acid ethyl ester, adipic acid methyl ester, adipic acidethyl ester), straight-chain or branched fatty alcohols and estersthereof, especially esters with acetic acid or lactic acid (e.g. ethyloleate, ethyl laurate, ethyl palmitate, ethyl lactate, propyl lactate,propyl palmitate, propyl laurate, propyl oleate), polyhydric aliphaticalcohols or polyethylene glycols, sorbitan fatty acid esters and theirderivatives obtained by ethoxylation, fatty alcohol ethoxylates,polyoxyethylene fatty acid ester; lauric acid diethanolamide, oleic aciddiethanolamide, coconut fatty acid diethanolamide, D-alpha-tocopherol,lauric acid hexyl ester, 2-octyldodecanol, dexpanthenol, isopropylideneglycerol, transcutol (=diethylene glycol monoethyl ether), DEET(=N,N-diethyl-m-tolueneamide), solketal, ethanol, 1,2-propanediol orother short-chain alcohols (e.g. alcohols with up to 6 C atoms), as wellas menthol and other essential oils or components of essential oils. Tooptimize active substance flow, it is also possible to use combinationsof two or more enhancers.

The total constituent amount of plasticizers and permeation-enhancingsubstances may be up to 10%-wt, relative to the film-shaped medicamentform. Having a content of less than 5%-wt., especially less than 1%-wt.may also be employed.

Examples for solubilizers are polyhydric alcohols such as1,2-propanediol, butanediol, glycerol, polyethylene glycol 400,tetrahydrofurfuryl alcohol, diethylene glycol monoethyl ether, diethyltoluamide and monoisopropylidene glycerol. The portion of thesolubilizers(s), relative to a medicament form, can be between 0.1 and10%-wt, or even 0.5 to 5%-wt.

Suitable as pigments are, in particular, talcum, titanium dioxide, ironoxide or lamellar pigments. The pigment portion can amount to up to 80,or even up to 70%-wt, relative to the polymer portion in the respectivelayer.

As shown in FIG. 1, the inventive film-shaped mucoadhesive systems areconstructed, in the simplest case, of two layers, namely a mucoadhesivelayer 2 and a backing layer 3 connected to said backing layer 3. Backinglayer 3 may serve as an active substance reservoir. In addition, themucoadhesive layer 2 may also contain active substance, such as the sameactive substance as contained in the backing layer 3.

The active substance release from the system 1 to the mucosa 4 takesplaces by diffusion from the layers of the system 1.

According to one embodiment of the present invention, the backing layer3 is modified by suitable additives in such a manner that the permeationof water and the diffusion of active substance in backing layer 3 isreduced or blocked, relative to the diffusion and permeation in themucoadhesive layer 2.

In further embodiments of the invention, the systems may be designed asmultilayer systems and can contain up to 6 individual layers, such aswith a layer number of 2 to 4. In each case, one of the surfaces of thesystem is formed by a mucoadhesive layer 2. All of the layers maycontain the same active substance, at the same or differentconcentrations.

The multilayered structure enables the manufacture of inventive systemswhich immediately after application release an initial burst dose andsubsequently release a maintenance dose at a reduced delivery rate overa prolonged period of time (several hours, preferably 0.5 to 24 hours).

Especially advantageous are embodiments wherein the backing layer 3 isconstructed of two or more individual layers 3 a, 3 b which aresuperimposed one upon another and are connected with one another. Inthis way it is possible to increase the active substance dose containedin the system 1. In addition, the individual layers may containadditives which modify the solubility and the diffusion coefficient ofthe active substance in the respective layer. Thereby, a multilayer isobtained which has a defined concentration gradient. This embodiment isparticularly advantageous. The formation of a concentration gradientcan, in addition, be assisted by providing the active substance in theindividual layers in increasing or decreasing amounts or concentrations.

According to an additional embodiment of the present invention, it isprovided that the backing layer 3 or that outer layer which is locatedon the side of the system that is opposite the mucoadhesive layer 2 andforms the outer surface, is modified by suitable additives such that thepermeation of water and the diffusion of active substance in this layeris reduced or blocked, relative to the diffusion and permeation in themucoadhesive layer 2 or in the other layers of the backing layer 3.

In this manner, a transmucosal system 1 is obtained which has astructure of at least three layers, namely comprising a mucoadhesivelayer 2, at least one middle reservoir layer 3 a connected to saidmucoadhesive layer 2, and an outer layer or boundary layer 3 b connectedto said reservoir layer 2 (FIG. 2). In the latter layer, the diffusionof active substance—relative to the middle layer(s)—is reduced or evencompletely blocked.

The modification of the diffusion and permeation properties can bebrought about, in particular, by varying the pigment content or/and byadmixing suitable diffusion-retarding polymeric (e.g. ethyl cellulose,propyl cellulose) or non-polymeric auxiliary substances. In this manner,it is possible to adjust the diffusion properties of the backing layer3, respectively the outermost layer 3 b of the backing layer 3, betweentwo extremes, namely between complete blockage of the diffusion on theone hand, and practically unimpeded or unmodified active substancediffusion from the matrix. Thus it is possible to optionally manufacturesystems which release the active substance(s) on one side (i.e. only onthe mucoadhesive side) or on two sides (i.e. on the mucoadhesive sideand on that side of the system which is opposite thereto).

At least the middle layer(s) 3 a of the system contain(s) the activesubstance. Outer boundary layer 3 b may contain the same activesubstance(s). In addition, the mucoadhesive layer 2 may also contain anactive substance.

With the above described, at least three-layered structure comprisingthe outer layer 3 b, a system 1 is obtained wherein the delivery ofactive substance is controlled by a combination of matrix-controlleddiffusion and membrane-controlled release.

Generally such a system, which is based on a mixed control (combinationof matrix and membrane control) would release the active substance in akind of saturation function, i.e. the delivery rate of the system woulddecrease further and further as the exhaustion of the system increases.By a suitable formulation, especially by a suitable selection of thematrix polymer(s) (increasing the portion of hydrophile functionalgroups), or by adding suitable hydrophile, water-binding additives(especially polyalcohols or polymeric surfactants with high HLB value,such as HLB≧10, or even HLB≧15), it is possible to influence andincrease the degree of water uptake or the degree of swelling of thereservoir layer with increasing retention time of the system in themoist medium (i.e. at the application site in the oral cavity).

By the above-described measures, the diffusion coefficient in thereservoir layer 3 can be increased by an increase in the swelling or byan increase in the degree of hydration. It is thereby possible tocompensate the decrease in the release rate, caused by the decrease ofthe concentration gradient, by an increase in the swelling and hydrationof the active substance matrix such that a release results which isessentially linear, this is accompanied by a high exhaustion of thesystem.

These properties of the systems according to the invention are ofsignificance especially with a view to a prolonged application of thesystem, for instance over a period of several hours (e.g. 2 to 24 h).This is true, in particular, where the substances to be administeredhave a correspondingly narrow therapeutic window.

At least one of the layers of the inventive film-shaped systems 1contains an active substance or a combination of active substances. Thepolymers of the individual layers form a polymer matrix which may serveas an active substance reservoir. In this polymer matrix the activesubstance(s) are already contained, in dissolved, suspended oremulsified form, whereby “dissolved” is in the sense of a “solidsolution”. Suitable as active substances are, in particular, medicinalsubstances, such as highly efficacious medicinal substances, e.g. fromthe following groups: agents acting on the nervous system,psychopharmacological agents, sedatives, narcotics, hormones,insulin-like active agents, analgesics, anticonvulsives, anti-parkinsonagents, medicaments acting on the cardiovascular system,anti-infectives, active agents for treating metabolic disturbances (e.g.lipid-lowering agents), agents acting on the muscular system, andothers.

The inventive systems are suitable above all for administeringmedicaments that are subject to rapid metabolism or/and are absorbedonly insufficiently via the gastrointestinal route.

The invention is further explained in the following examples.

EXAMPLE

Preparation of a Three-Layered System (as in FIG. 2)

An active substance is dissolved in a neutral polyacrylate (e.g.EUDRAGIT® NE 30 D; Röhm), either directly or employing a suitablesolvent known to those skilled in the art, if need be by using adissolving intermediary or solubilizer. The selection of the suitablemethod is dependent on the solubility, respectively the dissolvingproperties of the active agent employed.

Furthermore, an appropriate pigment is added to the activesubstance-containing polymer solution, e.g. talcum, TiO₂, iron oxide orlamellar pigments, and a homogenous liquid is prepared. The pigmentcontent is relatively high and is at approx. 60%-wt, relative to thepolymer portion.

Subsequently, the viscosity of the liquid is adjusted such that it issuitable for the subsequent processing steps. The liquid is applied by acasting method or spraying method to an inert support and is subjectedto subsequent drying which results in a thin film. The inert supportemployed must be such that the film remains adhering thereto afterdrying, but can be detached from the support without being destroyed.

In the same manner as above-described, a second liquid is prepared whichdiffers from the first formulation only in that it does not contain thepigment or contains a lower portion of pigment. Thereby, the activesubstance content is increased relative to the entire solids content, ascompared to the liquid prepared first. The second liquid is coated,again by means of a spraying or casting method, onto the layer preparedfirst and is subsequently dried so that a two-layer laminate with tworeservoir layers is obtained.

To prepare the mucoadhesive layer, an aqueous solution of highlyhydrolyzed polyvinyl alcohol (e.g. MOWIOL® 28-99, Clariant) of suitableconcentration (e.g. 10%-wt.; optionally 0.5 to 60%-wt) is prepared, anda suitable portion of adhesive polymer (e.g. GANTREZ® S 95; ISP) isdissolved therein. The portion of adhesive polymer in this examplecorresponds to the polyvinyl alcohol portion (that is, mixing ratio 1:1;weight content). But other mixing ratios can be employed as well, e.g.in the range of 50:1 to 1:50, relative to the portion of adhesive: theportion of polyvinyl alcohol).

The resultant homogenous solution is coated, again employing a suitableapplication method, onto the previously prepared two-layer laminate, andsubsequently dried.

This yields a three-layer laminate which—depending on the coatingWeight—is approx. 50 to 250 μm in thickness. The top side of thislaminate has good tackiness in moist state and has mucoadhesiveproperties. The laminate as a whole has very good flexibility andadheres to a mucosa for several hours after application thereof.

The inventive transmucosal systems are advantageously suitable foradministering active agents, especially medicaments, for therapeutic orprophylactic treatment in human or veterinary medicine.

What has been described above are preferred aspects of the presentinvention. It is of course not possible to describe every conceivablecombination of components or methodologies for purposes of describingthe present invention, but one of ordinary skill in the art willrecognize that many further combinations and permutations of the presentinvention are possible.

Accordingly, the present invention is intended to embrace all suchalterations, combinations, modifications, and variations that fallwithin the spirit and scope of the appended claims.

I claim:
 1. A process for treating a patient by medicinal therapy comprising the steps of: applying a film-shaped therapeutic system comprising at least three layers connected with each other for transmucosal administration of active substances, onto the oral mucosa of a patient in need of medicinal therapy for a period of up to 24 hours, wherein said at least three layers include: a mucoadhesive layer which is mucoadhesive in an aqueous environment; and a backing layer comprising at least one neutralized polymethyl methacrylate and containing an active substance and a pigment, wherein said backing layer is at least two-layered and comprises a middle layer disposed upon said mucoadhesive layer and an outer layer, wherein one of said layers of said at least two-layered backing layer does not contain said pigment or contains a lower portion of said pigment than is contained in the respective other layer or layers of said at least two-layered backing layer; wherein said mucoadhesive layer swells in an aqueous medium but is insoluble or poorly soluble in the aqueous medium and contains a polymer mixture comprising at least one hydrophilic mucoadhesive polymer embedded or dispersed in a matrix comprising at least one polyvinyl alcohol, said at least one hydrophilic mucoadhesive polymer being poly(methyl vinyl ether maleic anhydride); wherein said pigment is provided in one layer of said at least two-layered backing layer in an amount in the range of 60 wt. %-80 wt. % relative to the polymer portion in the layer, wherein said pigment is provided in one layer of said at least two-layered backing layer in an amount less than that of the other layer or layers of said at least two-layered backing layer; and wherein the weight ratio of said at least one hydrophilic mucoadhesive polymer to said polyvinyl alcohol is in the range of 50:1 to 1:50, and releasing the active substance, wherein the active substance is released by an initial burst dose and a subsequent maintenance dose released at a reduced delivery rate relative to the initial burst dose over a period of time.
 2. The process according to claim 1, wherein the step of releasing the active substance comprises a release period of 0.5 hour to 24 hours.
 3. The process according to claim 1, wherein the step of applying the film-shaped therapeutic system comprises maintaining said film-shaped therapeutic system on the oral mucosa of a patient for a period of up to 6 hours.
 4. The process according to claim 1, wherein one of the layers of said at least two-layered backing layer contains a lower portion of said pigment than is contained in the respective other layer of said at least two-layered backing layer.
 5. The process according to claim 1, wherein said mucoadhesive layer contains at least one active substance.
 6. The process according to claim 1, wherein said mucoadhesive layer further contains at least one mucoadhesive polymer selected from the group consisting of polyacrylates and salts of polyacrylates.
 7. The process according to claim 1, wherein said mucoadhesive layer further contains at least one mucoadhesive polymer selected from the group consisting of carboxymethyl cellulose and salts of carboxymethyl cellulose.
 8. The process according to claim 1, wherein said mucoadhesive layer further contains at least one mucoadhesive polymer selected from the group consisting of carboxyl groups-carrying hydrophilic adhesive polymers.
 9. The process according to claim 1, wherein said mucoadhesive layer further contains at least one mucoadhesive polymer selected from the group consisting of polymers of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol.
 10. The process according to claim 1, wherein the polymers of the mucoadhesive layer are cross-linked by physical or chemical methods.
 11. The process according to claim 1, wherein said system comprises four to six layers.
 12. The process according to claim 1, wherein at least two layers contain the same active substance at different concentrations such that a concentration gradient is formed.
 13. The process according to claim 1, wherein said pigment is selected from the group consisting of talcum, TiO₂, iron oxide and lamellar pigments.
 14. The process according to claim 1, wherein the system is a three-layered laminate having a thickness of 50 to 250 μm.
 15. The process according to claim 1, wherein two adjacent layers of said at least two-layered backing layer which are in contact with each other contain polymers selected from the group consisting of polyacrylates.
 16. The process according to claim 1, wherein said middle layer disposed upon said mucoadhesive layer contains said active substance.
 17. The process according to claim 1, wherein said middle layer disposed upon said mucoadhesive layer and said outer layer contain said active substance.
 18. The process according to claim 1, wherein the weight ratio of said at least one hydrophilic mucoadhesive polymer and said polyvinyl alcohol is 1:1.
 19. The process according to claim 1, wherein said outer layer of said at least two-layered backing layer further contains polymeric auxiliary substances selected from the group consisting of ethyl cellulose and propyl cellulose.
 20. The process according to claim 1, wherein said backing layer contains at least one of the following selected from the group consisting of at least one plasticizer, at least one penetration enhancer/permeation enhancing substance and at least one solubilizer.
 21. The process according to claim 1, wherein the backing layer forms a boundary layer wherein the permeation of water and the diffusion of active substance is reduced in the boundary layer relative to the other layers of said film-shaped therapeutic system.
 22. The process according to claim 21, wherein the outermost layer of said at least two-layered backing layer relative to said mucoadhesive layer forms a boundary layer, and wherein the permeation of water and the diffusion of active substance in the boundary layer is reduced relative to the other layers of said film-shaped therapeutic system.
 23. The process according to claim 1, wherein said film-shaped therapeutic system comprises at least three layers, comprising said mucoadhesive layer, at least one middle layer, and an outermost backing layer, wherein said at least one middle layer is a middle reservoir layer, and wherein said outermost backing layer forms a boundary layer for reducing the permeation of water and diffusion of active substance relative to the other layers of said film-shaped therapeutic system.
 24. The process according to claim 23, wherein said outermost backing layer is a boundary layer and contains additives for reducing or blocking the diffusion of the active substance, the additives being selected from the group consisting of pigments and diffusion-retarding polymers.
 25. The process according to claim 23, wherein said at least one middle reservoir layer contains at least one additive for increasing the swelling capacity and the hydration of the reservoir matrix, and wherein said additives are hydrophilic water-binding substances.
 26. The process according to claim 25, wherein said hydrophilic water-binding substances are selected from the group consisting of poly-alcohols and polymeric surfactants with an HLB value of greater than or equal to
 10. 27. The process according to claim 1, wherein the active substances are present in a form selected from the group consisting of dissolved, suspended and emulsified.
 28. The process according to claim 1, wherein the at least three layers comprise additives for modifying the solubility and the diffusion coefficient of the active substance in the respective layer.
 29. The process according to claim 1, wherein said pigment is provided in an amount in the range of 60 wt. % -70 wt. % relative to the polymer portion in the respective layer.
 30. The process according to claim 20, wherein the total constituent amount of said at least one plasticizer and said at least one penetration enhancer/permeation enhancing substance is up to 10 wt. % relative to the film-shaped therapeutic system.
 31. The process according to claim 20, wherein the total constituent amount of said at least one plasticizer and said at least one penetration enhancer/permeation enhancing substance is less than 5 wt. % relative to the film-shaped therapeutic system.
 32. The process according to claim 31, wherein the total constituent amount of said at least one plasticizer and said at least one penetration enhancer/permeation enhancing substance is less than 1 wt. % relative to the film-shaped therapeutic system.
 33. The process according to claim 20, wherein said at least one plasticizer is at least one selected from the group consisting of hydrocarbons, alcohols, polyhydric alcohols, polyethylene glycols, triglycerides, carboxylic acids, ethers, esters and amines.
 34. The process according to claim 33, wherein said alcohols are higher alcohols selected from the group consisting of dodecanol, undecanol and octanol, and wherein said esters are selected from the group consisting of diethyl phthalate esters, n-butyl adipate esters and citric acid esters.
 35. The process according to claim 20, wherein said at least one penetration enhancer/permeation enhancing substance is at least one selected from the group consisting of saturated or unsaturated fatty acids, fatty acid esters, straight-chain or branched fatty alcohols and esters thereof, polyhydric aliphatic alcohols, polyethylene glycols, sorbitan fatty acid esters and their derivatives obtained by ethoxylation, fatty alcohol ethoxylates, polyoxyethylene fatty acid ester, lauric acid diethanolamide, oleic acid diethanolamide, coconut fatty acid diethanolamide, D-alpha-tocopherol, lauric acid hexyl ester, 2-octyldodecanol, dexpanthenol, isopropylidene glycerol, transcutol (diethylene glycol monoethyl ether), DEET (N,N-diethyl-m-tolueneamide), solketal, ethanol, 1,2-propanediol or other short-chain alcohols, menthol and other essential oils.
 36. The process according to claim 35, wherein said fatty acid esters are selected from the group consisting of esters with methanol, ethanol or isopropanol, wherein said straight-chain or branched fatty alcohols and esters thereof are selected from the group consisting of esters with acetic acid or lactic acid, and wherein said 1,2-propanediol or other short-chain alcohols are selected from the group consisting of alcohols with up to six carbon atoms.
 37. The process according to claim 36, wherein said esters with methanol, ethanol or isopropanol are selected from the group consisting of oleic acid ethyl ester, oleic acid methyl ester, lauric acid methyl ester, lauric acid ethyl ester, adipic acid methyl ester, and adipic acid ethyl ester, and wherein said esters with acetic acid or lactic acid are selected from the group consisting of ethyl oleate, ethyl laurate, ethyl palmitate, ethyl lactate, propyl lactate, propyl palmitate, propyl laurate, and propyl oleate.
 38. The process according to claim 20, wherein said at least one solubilizer is at least one polyhydric alcohol.
 39. The process according to claim 38, wherein said at least one polyhydric alcohol is selected from the group consisting of 1,2-propanediol, butanediol, glycerol, polyethylene glycol 400, tetrahydrofurfuryl alcohol, diethylene glycol monoethyl ether, diethyl toluamide and monoisopropylidene glycerol.
 40. The process according to claim 20, wherein the portion of said at least one solubilizer relative to the film-shaped therapeutic system is in the range of about 0.1 wt. % - 10 wt. %.
 41. The process according to claim 40, wherein the portion of said at least one solubilizer relative to the film-shaped therapeutic system is in the range of about 0.5 wt. % - 5 wt. %.
 42. A process for treating a patient by medicinal therapy comprising the steps of: applying a three-layered film-shaped therapeutic system wherein each layer is connected with an adjacent layer for transmucosal administration of active substances, onto the oral mucosa of a patient in need of medicinal therapy for a period of up to 24 hours, wherein at least one layer of said three-layered film-shaped therapeutic system comprises at least one active substance, and wherein said three-layered film-shaped therapeutic system comprises: a mucoadhesive layer which is mucoadhesive in an aqueous environment; and a two-layered backing layer, said two-layered backing layer comprising at least one neutralized polymethyl methacrylate and containing an active substance and a pigment, wherein said two-layered backing layer comprises a middle layer relative to said three-layered film-shaped therapeutic system being disposed upon said mucoadhesive layer, and an outer layer disposed upon the layer that is disposed upon said mucoadhesive layer, wherein one of said layers of said two- layered backing layer does not contain said pigment or contains a lower portion of said pigment than is contained in the respective other layer of said two-layered backing layer; wherein said mucoadhesive layer swells in an aqueous medium but is insoluble or poorly soluble in the aqueous medium and contains a polymer mixture comprising at least one hydrophilic mucoadhesive polymer embedded or dispersed in a matrix comprising at least one polyvinyl alcohol, said at least one hydrophilic mucoadhesive polymer being poly(methyl vinyl ether maleic anhydride); wherein said pigment is provided in one layer of said two-layered backing layer in an amount in the range of 60-80 wt. %. relative to the polymer portion in the layer; wherein said pigment is provided in one layer of said two-layered backing layer in an amount less than that of the other layer of said two-layered backing layer; and wherein the weight ratio of said at least one hydrophilic mucoadhesive polymer to said polyvinyl alcohol is in the range of 50:1 to 1:50, and releasing the active substance, wherein the active substance is released by an initial burst dose and a subsequent maintenance dose released at a reduced delivery rate relative to the initial burst dose over a period of time.
 43. The process according to claim 42, wherein said pigment provided in one layer of said two-layered backing layer is provided in an amount of 60 wt. % relative to the polymer portion in the layer. 